Safety and Efficacy of Lenvatinib Treatment in Child–Pugh A and B Patients with Unresectable Hepatocellular Carcinoma in Clinical Practice: A Multicenter Analysis

Figures & data

Figure 1 Flow chart showing patient enrollment in the study.

Table 1 Baseline Characteristics of Patients

	Total cases (n=181)	CP-A cases (n=126)	CP-B cases (n=55)	P value
Age, years (range)	72 (34-90)	74 (34-90)	70 (46-84)	0.032
Sex (Male/Female),  n (%)	140/41 (77.3/22.7%)	95/31 (75.4/24.6%)	45/10 (81.8/18.2%)	0.44
Cause of HCC (HBV/ HCV/NBNC), n (%)	43/64/74 (23.8/35.4/40.9%)	30/46/50 (23.8/36.5/39.7%)	13/18/24 (23.6/32.7/43.6%)	0.86
BMI (kg/m2) (range)	23.1 (15.0-39.3)	23.3 (22.5-39.3)	22.9 (15.0-34.9)	0.62
Child-Pugh class (A/B), n (%)	126/55 (69.6/30.4%)
CP score (5/6/7/8), n (%)	75/51/36/19 (41.4/28.2/19.9/10.5%)	75/51/0/0 (59.5/40.5/0/0%)	0/0/36/19 (0/0/65.5/34.5%)	<0.001
mALBI (1+2a/2b+3), n (%)	98/83 (54.1/45.9%)	95/31 (75.4/24.6%)	3/52 (5.5/94.5%)	<0.001
PS (0/1/2), n (%)	145/34/2 (80.1/18.8/1.1%)	102/23/1 (81.0/18.3/0.8%)	43/11/1 (78.2/20.0/1.8%)	0.71
Extrahepatic metastasis, n (%)	65 (35.9%)	51 (40.5%)	14 (25.5%)	0.064
MVI (Vp1+Vp2/Vp3/Vp4), n (%)	25/13/17 (13.8/7.2/9.4%)	16/8/9 (12.7/6.3/7.1%)	9/5/8 (16.4/9.1/14.5%)	0.079
HCC occupying ≥ 50% of the liver, n (%)	18 (9.9%)	12 (9.5%)	6 (10.9%)	0.79
BCLC stage (B/C), n (%)	82/99 (45.3/54.7%)	57/69 (45.2/54.8%)	25/30 (45.5/54.5%)	1
TKI 1st line / 2nd line/ 3rd line-, n (%)	148/16/17 (81.8/8.8/9.4%)	108/9/9 (85.7/7.1/7.1%)	40/7/8 (72.7/12.7/14.5%)	0.124
Past history of TACE, n (%)	145 (80.1%)	96 (76.2%)	49 (89.1%)	0.066
AFP (ng/mL) (range)	69.3 (0-507689)	44.0 (0.8-262413)	384.1 (0-507689)	0.034
DCP (AU/mL) (range)	772 (3-290000)	674.5 (3-290000)	1075 (16-80090)	0.26
Observation period, days (range)	194 (22-461)	199 (28-461)	144 (22-405)	0.013

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; BMI, body mass index; CP, Child-Pugh; mALBI grade, modified albumin‐bilirubin grade; PS, Eastern Cooperative Oncology Group performance status; MVI, major venous invasion; BCLC, Barcelona clinic liver cancer; TKI, tyrosine kinase inhibitor; TACE, transcatheter arterial chemoembolization; AFP, alpha‐fetoprotein; DCP, des-gamma-carboxy prothrombin.

Table 2A Comparison of Adverse Events According to CP Class

		CP-A (n=126)		CP-B (n=55)		P value
Total treatment-related adverse events	Any grade	124	(98.4%)	52	(94.5%)	0.165
	Grade≥3	71	(56.3%)	25	(45.5%)	0.197
Decreased appetite	Any grade	65	(51.6%)	38	(69.1%)	0.034
	Grade≥3	13	(10.3%)	2	(3.6%)	0.156
Fatigue	Any grade	62	(49.2%)	31	(56.4%)	0.42
	Grade≥3	9	(7.1%)	1	(1.8%)	0.29
Proteinuria	Any grade	54	(42.9%)	12	(21.8%)	0.007
	Grade≥3	12	(9.5%)	0	(0.0%)	0.019
Hypertension	Any grade	53	(42.1%)	21	(38.2%)	0.74
	Grade≥3	7	(5.6%)	4	(7.3%)	0.74
Hand-foot skin reaction	Any grade	45	(35.7%)	19	(34.5%)	1.00
	Grade≥3	7	(5.6%)	2	(3.6%)	0.73
Elevated aspartate aminotransferase	Any grade	45	(35.7%)	14	(25.5%)	0.23
	Grade≥3	6	(4.8%)	1	(1.8%)	0.68
Hypothyroidism	Any grade	32	(25.4%)	12	(21.8%)	0.71
	Grade≥3	3	(2.4%)	1	(1.8%)	1.00
Decreased platelet count	Any grade	28	(22.2%)	7	(12.7%)	0.157
	Grade≥3	9	(7.1%)	2	(3.6%)	0.51
Dysphonia	Any grade	26	(20.6%)	8	(14.5%)	0.41
	Grade≥3	0	(0.0%)	0	(0.0%)	1.00
Diarrhea	Any grade	25	(19.8%)	19	(34.5%)	0.040
	Grade≥3	3	(2.4%)	1	(1.8%)	1.00
Constipation	Any grade	18	(14.3%)	5	(9.1%)	0.47
	Grade≥3	2	(1.6%)	2	(3.6%)	0.59
Increased serum bilirubin	Any grade	15	(11.9%)	15	(27.3%)	0.016
	Grade≥3	3	(2.4%)	2	(3.6%)	0.64
Weight loss	Any grade	14	(11.1%)	10	(18.2%)	0.24
	Grade≥3	1	(0.8%)	0	(0.0%)	1.00
Abdominal pain	Any grade	9	(7.1%)	6	(10.9%)	0.39
	Grade≥3	2	(1.6%)	0	(0.0%)	1.00
Hepatic encephalopathy	Any grade	4	(3.2%)	9	(16.4%)	0.003
	Grade≥3	3	(2.4%)	3	(5.5%)	0.37
Bleeding symptoms	Any grade	7	(5.6%)	5	(9.1%)	0.52
	Grade≥3	7	(5.6%)	3	(5.5%)	1.00
Nausea	Any grade	6	(4.8%)	5	(9.1%)	0.092
	Grade≥3	1	(0.8%)	0	(0.0%)	1.00
Vomiting	Any grade	3	(2.4%)	7	(12.7%)	0.009
	Grade≥3	0	(0.0%)	0	(0.0%)	1.00

Abbreviations: All values are expressed as the number (%)

Notes: C-P A, Child-Pugh grade A; C-P B, Child-Pugh grade B

Table 2B Comparison of Adverse Events According to CP Class

	CP-A (n=126)		CP-B (n=55)		*/**
	Treatment withdrawal	Treatment interruption or withdrawal	Treatment withdrawal	Treatment interruption or withdrawal
Total treatment-related adverse events	50 (39.7%)	82 (65.1%)	23 (41.8%)	33 (60.0%)	0.87/0.74
Decreased appetite	12 (9.5%)	13 (10.3%)	5 (9.1%)	5 (9.1%)	0.78/0.66
Proteinuria	8 (6.3%)	12 (9.5%)	1 (1.8%)	1 (1.8%)	0.28/0.042
Bleeding symptoms	6 (4.8%)	7 (5.6%)	3 (5.5%)	3 (5.5%)	1/1
Fatigue	4 (3.2%)	9 (7.1%)	3 (5.5%)	3 (5.5%)	0.44/0.56
Hepatic encephalopathy	3 (2.4%)	3 (2.4%)	4 (7.3%)	5 (9.1%)	0.20/0.057
Hand-foot syndrome	5 (4.0%)	7 (5.6%)	1 (1.8%)	2 (3.6%)	0.67/1
Decreased platelet count	4 (3.2%)	9 (7.1%)	0 (0.0%)	2 (3.6%)	0.32/0.51
Hypothyroidism	3 (2.4%)	3 (2.4%)	0 (0.0%)	1 (1.8%)	1/1
Diarrhea	1 (0.8%)	3 (2.4%)	1 (1.8%)	1 (1.8%)	0.52/1
Elevated aspartate aminotransferase	2 (1.6%)	6 (4.8%)	0 (0.0%)	1 (1.8%)	1/0.68
Increased blood bilirubin	1 (0.8%)	3 (2.4%)	1 (1.8%)	2 (3.6%)	1/0.64
Hypertension	0 (0.0%)	7 (5.6%)	1 (1.8%)	4 (7.3%)	0.30/0.74
Other reasons	10 (7.9%)	18 (14.3%)	5 (9.1%)	9 (16.4%)	0.78/0.82

Abbreviations: All values are expressed as number (%)

Notes: CP-A, Child-Pugh A; CP-B, Child-Pugh B *: P value of withdrawal between CP-A and B**: P value of interruption or withdrawal between CP-A and B

Figure 2 Radiological response as assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST) according to Child-Pugh (CP) class (A), CP score (B), modified albumin-bilirubin (mALBI)-grade (C) and Barcelona clinic liver cancer (BCLC) stage (D).

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not estimated.

Figure 3 Association between optimal relative dose intensity (RDI) and objective response (OR) following lenvatinib treatment. Receiver operating characteristic (ROC) curve analyses of the RDI up to 8 weeks (A). Difference in OR according to RDI up to 8 weeks (B). Difference in RDI up to 8 weeks according to Child-Pugh (CP) class (C). The box plots show the median and quartiles, and the whisker caps of the box plots show the mean 10th and 90th percentile values. RDI in CP-A and CP-B patients every month from the start of treatment to 2 months later (D). AUROC, area under the ROC revealed by ROC curve analysis.

Table 3 Factors Associated with Object Response

Factor		Multivariable analysis
		Odds Ratio	95%C.I.	P value
Age (years)	< 71	1.24	0.56-2.77	0.59
Sex	Male	0.81	0.32-2.04	0.65
HCV status	Positive	0.77	0.34-1.74	0.53
BMI (kg/m^2)	< 23.2	0.58	0.26-1.27	0.174
Child-Pugh class	A (vs. B)	2.72	1.02-7.24	0.045
PS	0 (vs. 1, 2)	4.00	1.18-13.5	0.026
Extrahepatic metastasis	Positive	1.08	0.31-3.73	0.90
MVI	Positive	1.05	0.37-2.98	0.93
Patients with > 50% liver occupation	Positive	2.91	0.66-12.8	0.157
BCLC stage	B (vs. C)	1.91	0.53-6.84	0.32
Past history of TKI	Experienced	2.23	0.74-6.75	0.155
Past history of TACE	Experienced	0.85	0.33-2.24	0.75
AFP (ng/mL)	< 69.3	0.90	0.41-2.00	0.79
DCP (mAU/mL)	< 772	2.02	0.86-4.73	0.106
RDI	> 0.70	2.40	1.07-5.39	0.034

Abbreviations: HCV, hepatitis C virus; BMI, body mass index; PS, Eastern Cooperative Oncology Group performance status; MVI, major venous invasion; BCLC, Barcelona clinic liver cancer; TKI, tyrosine kinase inhibitor; TACE, transcatheter arterial chemoembolization; AFP, alpha‐fetoprotein; DCP, des-gamma-carboxy prothrombin; RDI, relative dose intensity.

Figure 4 Association between overall survival (OS) and several clinical factors. Kaplan-Meier analysis of 181 hepatocellular carcinoma (HCC) patients who received lenvatinib treatment, stratified by Child-Pugh (CP) class (A), modified albumin-bilirubin (mALBI)-grade (B), CP score (C), CP score of 5–7 vs 8–9 (D) and Barcelona Clinic Liver Cancer (BCLC) stage (E). Kaplan–Meier analysis of 99 BCLC-C HCC patients who received lenvatinib treatment stratified by C-P class (F).

Table 4 Factors Associated with Overall Survival Time

Factor		Multivariable analysis
		HR	95%C.I.	P value
Age (years)	< 71	0.89	0.49-1.64	0.71
Child-Pugh class	A (vs. B)	0.41	0.21-0.78	0.007
PS	0 (vs. 1, 2)	1.14	0.56-2.3	0.72
BCLC stage	B (vs. C)	0.35	0.18-0.69	0.002
RDI	> 0.70	0.64	0.31-1.31	0.22

Abbreviations: HR, hazard ratio; PS, Eastern Cooperative Oncology Group performance status; BCLC, Barcelona clinic liver cancer; RDI, relative dose intensity.